The present invention relates to a therapeutic agent for rheumatic disease comprising an anti-Fas monoclonal antibody, or the combination of an anti-Fas monoclonal antibody and a medical substance having an inhibitory effect on cell proliferation as an active ingredient.
Among various rheumatic disorders, especially rheumatoid arthritis (RA) belongs to the group of diseases in which the basic pathogenesis is abnormal proliferation of synovial cells accompanied by various immunological disorders caused by internal and external factors and developed to bone and joint erosion.
RA is also characterized by regression of the hyperplastic synovium with subsequent replacement by fibrotic tissue (Fassbender HG: "Pathology of Rheumatic Diseases", Berlin, Heidelberg, Springer-Verlag, 1975), but the mechanisms of regression and replacement remain obscure. However, the destruction of tissue around morbid joints in RA is considered to be caused by abnormal production of cytokines from inflammatory synovial cells.
Synovial cells play an important role in RA in this way. For example, examining the findings of joint lesions with RA, an increase in synovial villi and multi-layerization of synovial cells have been observed and synovial cells are proliferated (Daniel J. McCarty, "Arthritis and Allied Conditions, A Textbook of Rheumatology", 11th Ed.).
If the proliferation of these synovial cells can be inhibited by a medical substance, it is thought to be a therapeutic agent for rheumatic disease.
At present, anti-inflammatory agents such as steroid, gold, and several cytotoxic agents are used for treating RA, but a medical substance which inhibits proliferation of synovial cells specifically is not known yet.
On the other hand, programmed cell death named "apoptosis" by Kerr et al., is distinct from necrosis (Br. J. Cancer, 26,239 (1972)). Necrosis of cells passes through a process accompanied by liberation of cytoplasmic contents, etc. because of hyperthermia, response to an antibody with complement, or chemical mediators. On the other hand, programmed cell death is observed in a certain group of cells programmed previously to die out in vivo, and it passes through a process termed apoptosis accompanied by phenomena such as bending of cell surface, condensation of nuclear chromatin, and chromosome DNA ladder formation.
Recently, Yonehara et al. reported an anti-Fas monoclonal antibody against a Fas antigen which is a cell membrane molecule concerned with apoptosis of immunocompetent cells (J. Exp. Med., 169, 1747 (1989)). Krammer et al. reported an anti-APO-1 antibody as an antibody which combines specifically with an antigen accompanied by apoptosis (Science, 245, 301 (1989)), but it was afterward confirmed that the antigens which these antibodies recognize are the same (Cell, 66, 233 (1991)).
Various studies were made about applications of the anti-Fas antibody including a therapeutic agent for AIDS and tumors (Japanese Patent Laid-open Publication No. 2-237935; WO 91/10448).
As described above, pathogenesis of RA is characterized by abnormal proliferation of synovial cells with infiltration of inflammatory cells and bone erosion. However, the proliferation of synovial cells is not limitless and spontaneous suppression of synovial proliferation is observed. Accordingly, it is necessary to study how alteration of rheumatoid synovial tissue occurs, whether the alteration is mediated by programmed cell death (apoptosis), and whether the Fas antigen exists in synovial cells. These studies are necessary to support this invention theoretically.
The subject of this invention is to develop a use for the anti-Fas monoclonal antibody as a therapeutic agent for rheumatic disease, especially as a therapeutic agent for rheumatoid arthritis, therefore, the following subject matters have to be studied.
1) Whether the anti-Fas monoclonal antibody can induce apoptosis in RA synovial cells, PA1 2) Whether the anti-Fas monoclonal antibody is effective for treatment of RA, PA1 3) Whether the anti-Fas monoclonal antibody does not cause severe side effects on other cells and organs.
If apoptosis is observed in RA synovial cells, if the abnormal proliferation of synovial cells can be inhibited by inducing apoptosis in synovial cells specifically, if the effectiveness of the medicine for human RA can be predicted, and if the medicine does not show severe side effects on other cells and organs, the medicine is expected to be a radical therapeutic agent for RA.
However, a medicine which induces apoptosis in synovial cells is not known yet, and it has been an important subject matter to find a medicine which inhibits the abnormal proliferation of synovial cells specifically.